AB0011 DNA METHYLATION AS A BIOMARKER OF TOCILIZUMAB RESPONSE IN RHEUMATOID ARTHRITIS PATIENTS
Authors: N. Nair, D. Plant, J. Isaacs, A. Morgan, K. Hyrich, A. Barton, A. G. Wilson
Journal: Annals of the Rheumatic Diseases (2022)

Background Tocilizumab (TCZ) is a disease-modifying antirheumatic biologic drug, which targets the IL-6 signalling pathway and is effective in ameliorating disease activity in rheumatoid arthritis (RA). However, approximately 50% of patients do not respond adequately to TCZ and some patients report adverse events. Considering there is growing evidence that DNA methylation is implicated in RA susceptibility and response to some biologics (1, 2), we investigated DNA methylation as a candidate biomarker for response to TCZ in RA. Objectives To identify differential DNA methylation signatures in whole blood associated with TCZ response in patients with RA. Methods Epigenome-wide DNA methylation patterns were measured using the Infinium EPIC 850k BeadChip (Illumina) in whole blood-derived DNA samples from patients with RA. DNA was extracted from blood samples taken pre-treatment and following 3 months on therapy, and response was determined at 6 months using the Clinical Disease Activity Index (CDAI). Patients who had good response (n=10) or poor response (n=10) to TCZ by 6 months were selected. Samples from secondary poor responders (n=10) (patients who had an improvement of CDAI and were in remission at 3 months, followed by a worsening of CDAI at 6 months) were also analysed. Differentially methylated positions (DMPs) were identified using linear regression, adjusting for gender, age, cell composition, smoking status, and glucocorticoid use. Results In the pre-treatment samples, 20 DMPs were significantly associated with response status at 6 months (unadjusted p-value &lt;10 -6 ), whilst in the 3 month samples, 21 DMPs were associated with response. One DMP, cg03121467, was significantly less methylated in good responders compared to poor responders in the pre-treatment samples. This DMP is close to EPB41L4A and may play a role in β–catenin signalling. Interestingly, cg10136146 was significantly less methylated in secondary poor responders compared to both good and poor responders in the 3 month samples. This DMP maps close to CD81 , which plays a role in mediating the development and activation of B and T lymphocytes. Conclusion These preliminary results provide evidence that DNA methylation patterns may predict response to TCZ. Further regional and pathway analyses is in progress and validation of these findings in other larger data sets is required. References [1]Liu,Y., Aryee,M.J., Padyukov,L., Fallin,M.D., Hesselberg,E., Runarsson,A., Reinius,L., Acevedo,N., Taub,M., Ronninger,M., et al. (2013) Epigenome-wide association data implicate DNA methylation as an intermediary of genetic risk in rheumatoid arthritis. Nat. Biotechnol. , 31 , 142–147. [2]Plant,D., Webster,A., Nair,N., Oliver,J., Smith,S.L., Eyre,S., Hyrich,K.L., Wilson,A.G., Morgan,A.W., Isaacs,J.D., et al. (2016) Differential Methylation as a Biomarker of Response to Etanercept in Patients With Rheumatoid Arthritis. Arthritis Rheumatol. (Hoboken, N.J. ), 68 , 1353–60. Disclosure of Interests Nisha Nair: None declared, Darren Plant: None declared, John Isaacs Speakers bureau: Abbvie, Gilead, Roche, UCB, Grant/research support from: GSK, Janssen, Pfizer, Ann Morgan Speakers bureau: Roche/Chugai, Consultant of: GSK, Roche, Chugai, AstraZeneca, Regeneron, Sanofi, Vifor, Grant/research support from: Roche, Kiniksa Pharmaceuticals, Kimme Hyrich Consultant of: AbbVie, Grant/research support from: Pfizer, BMS, Anne Barton Grant/research support from: I have received grant funding from Pfizer, Galapagos, Scipher Medicine and Bristol Myers Squibb., Anthony G Wilson: None declared